Elevated triglycerides and treatment eligibility in patients with severe, asymptomatic carotid stenosis: CREST 2 Trials.

BACKGROUND: Data from the Centers for Disease Control show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Some clinical trials, but not all, have demonstrated that pharmacologic treatment of high TG levels in patients already on statin therapy reduces the rate of major vascular events such as myocardial infarction and stroke. We assessed the prevalence of elevated TG levels in patients with asymptomatic carotid stenosis (CS), and medical conditions associated with high TG. METHODS: Baseline lipid profiles from patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. to determine treatment eligibility for high TG levels using the criteria established by the REDUCE-IT trial (triglyceride levels ≥150 mg/dL with LDL managed by a statin to <100 mg/dL). Equally assessed was the percentage of patients who were using pharmacologic treatment for high TG levels at study entry. Demographic factors and baseline medical conditions associated with high (>150 mg/dl) TG values were also analyzed. Chi-square and t=tests were used to assess baseline factors and abnormal TG values. RESULTS: As of October 2023, of 2377 randomized CREST-2 patients, 2328 (98 %) (mean age 70.0 years, 63 % men) had baseline lipid profiles suitable for analysis. Among 1961 (84 %) patients who met REDUCE-IT criteria, analysis of lipid profiles revealed that 20.5 % of the patients were eligible for treatment of high triglycerides. Of the 1464 patients with fasting lipid profiles, 17.8 % were eligible for treatment. The median TG value was 205 (IQR 91) mg/dl in the total population. TG levels of 150 mg/dl or higher were strongly associated with hypertension, diabetes, obesity, high hemoglobin A1c, and reduced physical activity (all p<0.0001). CONCLUSIONS: Elevated TG levels are strongly associated with diabetes, hypertension, obesity, and reduced physical activity. Further research is needed on whether treatment of elevated TG levels in patients with asymptomatic carotid stenosis confers benefit.

Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.

Larger A1/M1 diameter ratio predicts embolic anterior cerebral artery territorial stroke.

BACKGROUND AND PURPOSE: In contrast to middle cerebral artery territory strokes, anterior cerebral artery strokes (ACAS) occur rarely. The low frequency of ACAS, in relation to middle cerebral artery territory strokes, may be explained by differences in ACA and middle cerebral artery anatomy influencing their respective flow-directed embolism rates. We aimed to determine whether variability in ACA anatomy, and in particular A1 segment diameter, is associated with embolic ACAS. METHODS: Consecutive patients admitted to Boston Medical Center with embolic ACAS were reviewed. Ipsilateral and contralateral A1 diameters, M1 diameters, and terminal internal carotid artery bifurcation angles were measured from computed tomographic angiography and MRI angiography images. We compared these measurements between cases of ACAS and consecutive cases of embolic middle cerebral artery territory strokes. RESULTS: The study comprised 55 individuals (27 ACAS, 28 middle cerebral artery territory strokes) with mean age of 69 years. In multivariate regression analysis, larger ipsilateral A1 diameters (odds ratio per 1 mm increment: 8.5; 95% confidence interval, 1.4-53.3) and ipsilateral A1/M1 diameter ratio (odds ratio per 10% increment: 1.8; 95% confidence interval, 1.2-2.9) were associated with ACAS, whereas larger ipsilateral M1 diameters was protective for ACAS (odds ratio per 1 mm increment: 0.8; 95% confidence interval, 0.0-0.9). CONCLUSIONS: Larger ipsilateral A1 diameters and A1/M1 diameter ratio are associated with embolic ACAS. These findings suggest that A1 diameters and M1 diameters are important in determining the path of emboli that reach the terminal internal carotid artery.

Derivation of a clinical prediction score for the diagnosis of clinically significant symptomatic carotid artery disease.

OBJECTIVES: Emergent vascular imaging identifies a subset of patients requiring immediate specialized care (i.e. carotid stenosis > 50%, dissection or free-floating thrombus). However, most TIA patients do not have these findings, so it is inefficient to image all TIA patients in crowded emergency departments (ED). Our objectives were to derive and internally validate a clinical prediction score for clinically significant carotid artery disease in TIA patients. METHODS: This was a planned secondary analysis of a prospective cohort study from 14 Canadian EDs. Among 11555 consecutive adult ED patients with TIA/minor stroke symptoms over 12 years, 9882 had vascular imaging and were included in the analysis. Our main outcome was clinically significant carotid artery disease, defined as extracranial internal carotid stenosis ≥ 50%, dissection, or thrombus in the internal carotid artery, with contralateral symptoms. RESULTS: Of 9882 patients, 888 (9.0%) had clinically significant carotid artery disease. Logistic regression was used to derive a 13-variable reduced model. We simplified the model into a score (Symcard [Symptomatic carotid artery disease] Score), with suggested cut-points for high, medium, and low-risk stratification. A substantial portion (38%) of patients were classified as low-risk, 33.8% as medium risk, and 28.2% as high risk. At the low-risk cut-point, sensitivity was 92.9%, specificity 41.1%, and diagnostic yield 1.7%. CONCLUSIONS: This simple score can predict carotid artery disease in TIA patients using readily available information. It identifies low-risk patients who can defer vascular imaging to an outpatient or specialty clinic setting. Medium-risk patients may undergo imaging immediately or with slight delay, depending on local resources. High-risk patients should undergo urgent vascular imaging.

RéSUMé: OBJECTIFS: L'imagerie vasculaire émergente permet d'identifier un sous-ensemble de patients nécessitant des soins spécialisés immédiats (c.-à-d. sténose carotidienne >50 %, dissection ou thrombus flottant). Cependant, la plupart des patients atteints de RTI ne présentent pas ces résultats, il est donc inefficace d'effectuer une imagerie de tous les patients atteints de RTI dans les services d'urgence (ER) surpeuplés. Nos objectifs étaient de calculer et de valider en interne un score de prédiction clinique pour la maladie carotide cliniquement significative chez les patients atteints d'une AIT MéTHODES: Il s'agissait d'une analyse secondaire planifiée d'une étude de cohorte prospective menée auprès de 14 DE canadiens. Parmi les 11555 patients adultes consécutifs atteints d'un EI présentant des symptômes d'AIT/AVC mineur au cours des 12 dernières années, 9882 ont reçu une imagerie vasculaire et ont été inclus dans l'analyse. Notre principal critère de jugement était la maladie carotide cliniquement significative, définie comme une sténose extracrânienne de la carotide interne à 50 %, une dissection ou un thrombus dans l'artère carotide interne, avec des symptômes contralatéraux. RéSULTATS: Sur 9882 patients, 888 (9,0 %) présentaient une maladie de l'artère carotide cliniquement significative. La régression logistique a été utilisée pour obtenir un modèle réduit à 13 variables. Nous avons simplifié le modèle en un score (Symcard [Symptomatic carotid artery disease] Score), avec des points de coupure suggérés pour la stratification à risque élevé, moyen et faible. Une proportion importante (38,0 %) des patients ont été classés à faible risque, 33,8 % à risque moyen et 28,2 % à risque élevé. Au seuil de faible risque, la sensibilité était de 92,9 %, la spécificité de 41,1 % et le rendement diagnostique de 1,7 %. CONCLUSIONS: Ce score simple permet de prédire la maladie de l'artère carotide chez les patients atteints d'AIT en utilisant des informations facilement disponibles. Il identifie les patients à faible risque qui peuvent reporter l'imagerie vasculaire à un établissement de consultation externe ou de spécialité. Les patients à risque moyen peuvent subir une imagerie immédiatement ou avec un léger délai, selon les ressources locales. Les patients à haut risque doivent subir une imagerie vasculaire urgente.

A Multicentre Prospective Cohort Study to Identify High-Risk Transient Ischemic Attack/Minor Stroke Patients Benefitting from Echocardiography.

BACKGROUND: We aimed to derive a clinical decision rule to identify patients with transient ischemic attack (TIA) or minor stroke most likely to benefit from echocardiography. METHODS: This multicentre prospective cohort study enrolled adults diagnosed with TIA/minor stroke in the emergency department who underwent echocardiograms within 90 days, from 13 Canadian academic emergency departments from October 2006 to May 2017. Our outcome was clinically significant echocardiogram findings. RESULTS: In 7149 eligible patients, a clinically significant finding was found in 556 (7.8%). There were a further 2421 (33.9%) with potentially significant findings. History of heart failure (adjusted odds ratio [OR], 3.9) or coronary artery disease (OR, 2.7) were the factors most strongly associated with clinically significant echocardiogram findings, whereas young age, male sex, valvular heart disease, and infarct (any age) on neuroimaging were modestly associated (OR, 1.3-1.9). The model combining these predictors into a score (range: 0-15), had a C-statistic of 0.67 (95% confidence interval [CI], 0.65-0.70). A cut point of 6 points or more classified 6.6% of cases as high likelihood, defined as > 15% for clinically significant echocardiogram findings. CONCLUSIONS: Echocardiography is a very useful test in the investigations of patients with TIA/minor stroke. We identified high-risk clinical features-combined to create a clinical decision rule-to identify which patients with TIA/minor stroke are likely to have clinically significant echocardiogram findings requiring an immediate change in management. These patients should have echocardiography prioritized, whereas others may continue to have echocardiography conducted in a less urgent fashion.

Stroke Prevention With Left Atrial Appendage Closure in Patients With Atrial Fibrillation and Prior Intracranial Hemorrhage.

Background: Oral anticoagulation (OAC) is deemed a relative contraindication after intracranial hemorrhage (ICH) if the cause cannot be eliminated and the risk of recurrence is high. That leaves atrial fibrillation (AF) patients at high risk of thromboembolic events. Endovascular left atrial appendage closure (LAAC) can be an alternative to OAC for patients requiring stroke prevention. Methods: We performed a retrospective single-centre analysis of 138 consecutive ICH patients with nonvalvular AF and high stroke risk who underwent LAAC between 2010 and 2022 at Vancouver General Hospital. We report the baseline characteristics, procedural results, and follow-up data, comparing the observed stroke/transient ischemic attack (TIA) rate with the predicted event rate based on their CHA2DS2-VASc scores. Results: The average age was 76.1 ± 8.5 years; the mean CHA2DS2-VASc score was 4.4 ± 1.5; and the mean HAS-BLED score was 3.7 ± 0.9. The procedural success rate was 98.6%, and the complication rate was 3.6% with no periprocedural death, stroke, or TIA. The antithrombotic regimen post-LAAC consisted of short-term dual antiplatelet therapy (1-6 months) followed by aspirin alone for a minimum of 6 months in 86.2%. At mean follow-up of 14.7 ± 13.7 months, 9 deaths (6.5%, 7 cardiovascular, 2 noncardiovascular), 2 strokes (1.4%), and 1 TIA (0.7%) had occurred. The annualized observed stroke/TIA rate was 1.8%, which was lower than the adjusted predicted stroke rate of 7.0% (95% confidence interval: 4.8%-9.2%). Two patients (1.5%) suffered another ICH (both on aspirin monotherapy). One device-related thrombus (0.7%) was confirmed and treated with OAC without sequelae. Conclusion: Endovascular LAAC is a feasible alternative to OAC for stroke prevention in patients with nonvalvular AF and prior ICH.

Contexte: L'anticoagulation par voie orale (ACO) est considérée comme une contre-indication relative après une hémorragie intracrânienne (HIC) si la cause ne peut être éliminée et si le risque de récidive est élevé. Les patients souffrant de fibrillation auriculaire (FA) sont donc exposés à un risque élevé d'événements thromboemboliques. La technique de fermeture percutanée de l'appendice auriculaire gauche (AAG) peut être une solution de rechange aux anticoagulants oraux en prévention des accidents vasculaires cérébraux (AVC). Méthodologie: Nous avons réalisé une analyse rétrospective unicentrique auprès de 138 patients consécutifs qui étaient atteints d'une HIC accompagnée d'une FA non valvulaire ainsi que d'un risque élevé d'AVC et qui ont subi une fermeture de l'AAG entre 2010 et 2022 à l'hôpital général de Vancouver. Nous présentons ici les caractéristiques initiales, les résultats de l'intervention et les données de suivi, en comparant le taux d'AVC/AIT (accident ischémique transitoire) observé avec le taux prédit d'événements sur la base de leurs scores CHA2DS2-VASc. Résultats: L'âge moyen était de 76,1 ± 8,5 ans. Le score CHA2DS2-VASc moyen était de 4,4 ± 1,5, et le score HAS-BLED moyen de 3,7 ± 0,9. Le taux de réussite de l'intervention a été de 98,6 % et le taux de complications de 3,6 %, sans décès périopératoires, ni AVC ou AIT. Le traitement antithrombotique après la fermeture de l'AAG consistait en une bithérapie antiplaquettaire de courte durée (de 1 à 6 mois), suivie de la prise d'aspirine seule pendant au moins 6 mois dans 86,2 % des cas. Après un suivi moyen de 14,7 ± 13,7 mois, 9 décès (6,5 %, 7 d'origine cardiovasculaire et 2 d'origine non cardiovasculaire), 2 AVC (1,4 %) et 1 AIT (0,7 %) sont survenus. Le taux annualisé d'AVC/AIT observé était de 1,8 %, ce qui est inférieur au taux prédit d'AVC après ajustement, soit 7,0 % (intervalle de confiance à 95 % : 4,8 % à 9,2 %). Deux patients (1,5 %) ont souffert d'une autre HIC (tous deux sous aspirine en monothérapie). Un thrombus lié au dispositif (0,7 %) a été confirmé et traité par anticoagulathérapie orale sans séquelles. Conclusion: La technique de fermeture de l'AAG représente une solution de rechange à l'anticoagulation par voie orale dans la prévention des AVC chez les patients souffrant de FA non valvulaire et ayant déjà subi une HIC.

Ninety-Day Stroke or Transient Ischemic Attack Recurrence in Patients Prescribed Anticoagulation in the Emergency Department With Atrial Fibrillation and a New Transient Ischemic Attack or Minor Stroke.

Background For patients with atrial fibrillation seen in the emergency department (ED) following a transient ischemic attack (TIA) or minor stroke, the impact of initiating oral anticoagulation immediately rather than deferring the decision to outpatient follow-up is unknown. Methods and Results We conducted a planned secondary data analysis of a prospective cohort of 11 507 adults in 13 Canadian EDs between 2006 and 2018. Patients were eligible if they were aged 18 years or older, with a final diagnosis of TIA or minor stroke with previously documented or newly diagnosed atrial fibrillation. The primary outcome was subsequent stroke, recurrent TIA, or all-cause mortality within 90 days of the index TIA diagnosis. Secondary outcomes included stroke, recurrent TIA, or death and rates of major bleeding. Of 11 507 subjects with TIA/minor stroke, atrial fibrillation was identified in 11.2% (1286, mean age, 77.3 [SD 11.1] years, 52.4% male). Over half (699; 54.4%) were already taking anticoagulation, 89 (6.9%) were newly prescribed anticoagulation in the ED. By 90 days, 4.0% of the atrial fibrillation cohort had experienced a subsequent stroke, 6.5% subsequent TIA, and 2.6% died. Results of a multivariable logistic regression indicate no association between prescribed anticoagulation in the ED and these 90-day outcomes (composite odds ratio, 1.37 [95% CI, 0.74-2.52]). Major bleeding was found in 5 patients, none of whom were in the ED-initiated anticoagulation group. Conclusions Initiating oral anticoagulation in the ED following new TIA was not associated with lower recurrence rates of neurovascular events or all-cause mortality in patients with atrial fibrillation.

Risk of stroke is low after transient ischemic attack presentation with isolated dizziness.

OBJECTIVE: Stroke presenting as dizziness is a diagnostic challenge in frontline settings, given the multitude of benign conditions that present similarly. The risk of stroke after episodic dizziness is unknown, leading to divergent guidance on optimal workup and management. Prior TIA risk scores have shown a history of dizziness is a negative predictor of subsequent stroke. Our objective was to assess the subsequent stroke risk within 90 days following emergency department assessment (ED) for isolated dizziness diagnosed as TIA during the index visit. METHODS: We conducted prospective, multicenter cohort studies at 13 Canadian EDs over 11 years. We enrolled patients diagnosed with TIA and compared patients with isolated dizziness to those with other neurological deficits. Our primary outcome was subsequent stroke within 90 days. Secondary outcomes were subsequent stroke within 2, 7, and 30 days, respectively, as well as subsequent TIA within 90 days. RESULTS: Only 4/483 (0.8%) patients with isolated dizziness had a stroke within 90 days compared to 320/11024 (2.9%) of those with any focal neurological sign or symptom (RR 0.29, 95% CI 0.11-0.76). Over the first 90 days, the two groups differ significantly in their probability of stroke (p = 0.007). Subsequent TIA was also significantly less common in the isolated dizziness group (1.7% vs. 5.6%, p = 0.001) with a relative risk of 0.30 (95% CI 0.15-0.60). CONCLUSION: The risk of subsequent stroke following ED presentation for TIA is low when the presenting symptoms are isolated dizziness.

RéSUMé: OBJECTIF: Les accidents vasculaires cérébraux (AVC) se présentant sous forme de vertiges constituent un défi diagnostique en première ligne, étant donné la multitude d'affections bénignes qui se présentent de la même manière. Le risque d'accident vasculaire cérébral (AVC) après des vertiges épisodiques est inconnu, ce qui donne lieu à des conseils divergents sur le bilan et la prise en charge optimaux. Des scores de risque d'AIT antérieurs ont montré que des antécédents de vertiges sont un facteur prédictif négatif d'accident vasculaire cérébral ultérieur. Notre objectif était d'évaluer le risque ultérieur d'accident vasculaire cérébral (AVC) dans les 90 jours suivant l'évaluation aux urgences d'un étourdissement isolé diagnostiqué comme un AIT lors de la visite de référence. MéTHODES: Nous avons mené des études de cohorte prospectives multicentriques dans 13 services d'urgence canadiens pendant 11 ans. Nous avons recruté des patients ayant reçu un diagnostic d'AIT et avons comparé les patients présentant des vertiges isolés à ceux présentant d'autres déficits neurologiques. Nous avons inscrit des patients ayant reçu un diagnostic d'AIT et comparé des patients ayant des étourdissements isolés à ceux présentant d'autres déficits neurologiques. Notre résultat primaire était l'AVC subséquent dans les 90 jours. Les résultats secondaires étaient l'AVC subséquent dans les 2, 7 et 30 jours, respectivement, ainsi que l'AIT subséquent dans les 90 jours. RéSULTATS: Seuls 4/483 (0,8 %) des patients présentant des vertiges isolés ont eu un AVC dans les 90 jours, contre 320/11 024 (2,9 %) de ceux présentant un signe ou symptôme neurologique focal (RR 0,29, IC 95 % 0,11-0,76). Au cours des 90 premiers jours, les deux groupes diffèrent significativement en termes de probabilité d'AVC (p = 0,007). L'AIT ultérieur était également significativement moins fréquent dans le groupe des vertiges isolés (1,7 % contre 5,6 %, p = 0,001) avec un risque relatif de 0,30 (IC 95 % 0,15-0,60). CONCLUSIONS: Le risque d'AVC ultérieur après une présentation aux urgences pour un AIT est faible lorsque les symptômes présentés sont des étourdissements isolés.

Changes in intracortical excitability after transient ischemic attack are associated with ABCD² score.

BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) is a brief ischemic episode characterized by rapid clinical resolution and not associated with permanent cerebral infarction. Whether changes in intracortical excitability persist and are related to clinical predictors of stroke risk after TIA remains unknown. METHODS: Participants were individuals with clinically resolved motor TIA with no structural lesions and healthy age-matched control participants. Single and paired-pulse transcranial magnetic stimulation was used to measure intracortical excitability. Recruitment curves for percent inhibition and facilitation were used to derive excitability thresholds. Correlations between threshold asymmetries and ABCD(2) score were performed. RESULTS: Results showed a significant 3-way interaction with reduced inhibition and enhanced facilitation in the affected compared with unaffected hemisphere after TIA. No significant differences were present in healthy participants. Asymmetries in intracortical inhibition and facilitation were significantly correlated with ABCD(2) score. CONCLUSIONS: The present study is the first, to our knowledge, to demonstrate altered intracortical inhibition and facilitation in the affected hemisphere after TIA. These changes occurred on average 2 weeks after clinical signs of TIA resolved and in the absence of structural lesions and were not present in healthy age-matched control participants. Furthermore, this study is the first, to our knowledge, to report that changes in intracortical excitability after TIA are associated with ABCD(2) score.

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke.

BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

Telmisartan to prevent recurrent stroke and cardiovascular events.

BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Predictors of neurologists confirming or overturning emergency physicians' diagnosis of TIA or stroke.

BACKGROUND: Transient ischemic attack (TIA) and non-disabling stroke are common emergency department (ED) presentations. Currently, there are no prospective multicenter studies determining predictors of neurologists confirming a diagnosis of cerebral ischemia in patients discharged with a diagnosis of TIA or stroke. The objectives were to (1) calculate the concordance between emergency physicians and neurologists for the outcome of diagnosing TIA or stroke, and (2) identify characteristics associated with neurologists diagnosing a stroke mimic. METHODS: This was a planned sub-study of a prospective cohort study at 14 Canadian EDs enrolling patients diagnosed with TIA or non-disabling stroke from 2006 to 2017. Logistic regression was used to identify factors associated with neurologists' diagnosis of cerebral ischemia. Our primary outcome was the composite outcome of cerebral ischemia (TIA or non-disabling stroke) based on the neurologists' assessment. RESULTS: The diagnosis of cerebral ischemia was confirmed by neurologists in 5794 patients (55.4%). The most common identified stroke mimics were migraine (18%), peripheral vertigo (7%), syncope (4%), and seizure (3%). Over a third of patients (38.4%) ultimately had an undetermined aetiology for their symptoms. The strongest predictors of cerebral ischemia confirmation were infarct on CT (OR 1.83, 95% CI 1.65-2.02), advanced age (OR comparing 75th-25th percentiles 1.67, 1.55-1.80), language disturbance (OR 1.92, 1.75-2.10), and smoking (OR 1.67, 1.46-1.91). The strongest predictors of stroke mimics were syncope (OR 0.59, 0.48-0.72), vertigo (OR 0.52, 0.45-0.59), bilateral symptoms (OR 0.60, 0.50-0.72), and confusion (OR 0.50, 0.44-0.57). CONCLUSION: Physicians should have a high index of suspicion of cerebral ischemia in patients with advanced age, smoking history, language disturbance, or infarcts on CT. Physicians should discriminate in which patients to pursue stroke investigations on when deemed at minimal risk of cerebral ischemia, including those with isolated vertigo, syncope, or bilateral symptoms.

RéSUMé: CONTEXTE: L'accident ischémique transitoire (AIT) et l'accident vasculaire cérébral (AVC) non invalidant sont des présentations courantes dans les services d'urgence. Actuellement, il n'existe pas d'études prospectives multicentriques déterminant les facteurs prédictifs de la confirmation par les neurologues d'un diagnostic d'ischémie cérébrale chez les patients sortis de l'hôpital avec un diagnostic d'AIT ou d'AVC. Les objectifs étaient de (1) calculer la concordance entre les urgentistes et les neurologues pour le résultat du diagnostic de l'AIT ou de l'AVC, et (2) identifier les caractéristiques associées au diagnostic par les neurologues d'une imitation d'AVC. MéTHODES: Il s'agissait d'une sous-étude planifiée d'une étude de cohorte prospective dans 14 services d'urgence canadiens recrutant des patients diagnostiqués avec un AIT ou un AVC non invalidant de 2006 à 2017. Une régression logistique a été utilisée pour identifier les facteurs associés au diagnostic d'ischémie cérébrale par les neurologues. Notre résultat principal était le résultat composite de l'ischémie cérébrale (AIT ou accident vasculaire cérébral non invalidant) selon l'évaluation des neurologues. RéSULTATS: Le diagnostic d'ischémie cérébrale a été confirmé par des neurologues chez 5 794 patients (55,4 %). Les imitateurs d'AVC identifiés les plus courants étaient la migraine (18 %), le vertige périphérique (7 %), la syncope (4 %) et les convulsions (3 %). Plus d'un tiers des patients (38,4 %) avaient finalement une étiologie indéterminée pour leurs symptômes. Les prédicteurs les plus forts de la confirmation de l'ischémie cérébrale étaient l'infarctus au scanner (OR 1.83, IC 95 % 1.65­2.02), l'âge avancé (OR comparant les 75e et 25e percentiles 1.67, 1.55­1.80), les troubles du langage (OR 1.92, 1.75­2.10) et le tabagisme (OR 1.67, 1.46­1.91). Les prédicteurs les plus forts d'imitateurs d'AVC étaient la syncope (OR 0.59, 0.48­0.72), le vertige (OR 0.52, 0.45­0.59), les symptômes bilatéraux (OR 0.60, 0.50­0.72) et la confusion (OR 0.50, 0.44­0.57). CONCLUSION: Les médecins devraient avoir un indice élevé de suspicion d'ischémie cérébrale chez les patients ayant un âge avancé, des antécédents de tabagisme, des troubles du langage ou des infarctus au scanner. Les médecins doivent distinguer les patients sur lesquels poursuivre des investigations sur un AVC lorsqu'ils sont jugés à risque minimal d'ischémie cérébrale, y compris ceux présentant des vertiges isolés, une syncope ou des symptômes bilatéraux.

Prospective validation of Canadian TIA Score and comparison with ABCD2 and ABCD2i for subsequent stroke risk after transient ischaemic attack: multicentre prospective cohort study.

OBJECTIVE: To validate the previously derived Canadian TIA Score to stratify subsequent stroke risk in a new cohort of emergency department patients with transient ischaemic attack. DESIGN: Prospective cohort study. SETTING: 13 Canadian emergency departments over five years. PARTICIPANTS: 7607 consecutively enrolled adult patients attending the emergency department with transient ischaemic attack or minor stroke. MAIN OUTCOME MEASURES: The primary outcome was subsequent stroke or carotid endarterectomy/carotid artery stenting within seven days. The secondary outcome was subsequent stroke within seven days (with or without carotid endarterectomy/carotid artery stenting). Telephone follow-up used the validated Questionnaire for Verifying Stroke Free Status at seven and 90 days. All outcomes were adjudicated by panels of three stroke experts, blinded to the index emergency department visit. RESULTS: Of the 7607 patients, 108 (1.4%) had a subsequent stroke within seven days, 83 (1.1%) had carotid endarterectomy/carotid artery stenting within seven days, and nine had both. The Canadian TIA Score stratified the risk of stroke, carotid endarterectomy/carotid artery stenting, or both within seven days as low (risk ≤0.5%; interval likelihood ratio 0.20, 95% confidence interval 0.09 to 0.44), medium (risk 2.3%; interval likelihood ratio 0.94, 0.85 to 1.04), and high (risk 5.9% interval likelihood ratio 2.56, 2.02 to 3.25) more accurately (area under the curve 0.70, 95% confidence interval 0.66 to 0.73) than did the ABCD2 (0.60, 0.55 to 0.64) or ABCD2i (0.64, 0.59 to 0.68). Results were similar for subsequent stroke regardless of carotid endarterectomy/carotid artery stenting within seven days. CONCLUSION: The Canadian TIA Score stratifies patients' seven day risk for stroke, with or without carotid endarterectomy/carotid artery stenting, and is now ready for clinical use. Incorporating this validated risk estimate into management plans should improve early decision making at the index emergency visit regarding benefits of hospital admission, timing of investigations, and prioritisation of specialist referral.

A randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, tolerability, and pharmacokinetic/pharmacodynamic effects of a targeted exposure of intravenous repinotan in patients with acute ischemic stroke: modified Randomized Exposure Controlled Trial (mRECT).

BACKGROUND AND PURPOSE: Repinotan hydrochloride is a serotonin (5-HT)(1A) receptor full agonist with evidence of neuroprotection in animal models of permanent and transient focal ischemia. The purpose of this Phase IIb study was to investigate the efficacy, safety, and tolerability of a targeted exposure to repinotan in patients with acute ischemic stroke. METHODS: This was a double-blind, placebo-controlled, parallel-group, multicenter study of 681 patients stratified according to whether or not tissue plasminogen activator was administered and then randomly assigned to treatment with repinotan or placebo. A continuous 72-hour intravenous infusion of repinotan or placebo was to be started within 4.5 hours from the onset of ischemic symptoms. A Point-of-Care test was used to adjust the infusion rate if appropriate. The goal of Modified Randomized Exposure Controlled Trial (mRECT) was to show whether repinotan is statistically superior to placebo (alpha or=85) at 3 months, using a Cochran-Mantel-Haenszel test. RESULTS: For the intention-to-treat population at 3 months, the response rate on the Barthel Index was 37.1% (127 of 342) for patients on repinotan and 42.4% (143 of 337) for patients taking the placebo (Cochran-Mantel-Haenszel probability value=0.149). No apparent safety concerns were identified. CONCLUSIONS: mRECT demonstrated the feasibility of conducting a rigorous trial using a short therapeutic window demanding clinical and radiographic criteria to optimize patient selection and a Point-of-Care test to achieve a targeted exposure to repinotan. The study failed to demonstrate a clinical benefit of repinotan. The development of repinotan in acute ischemic stroke was discontinued.

Delayed detection of atrial fibrillation after ischemic stroke.

BACKGROUND: Detection of atrial fibrillation (AF) after ischemic stroke is important because anticoagulation is indicated to reduce the risk of recurrent stroke. However, no consensus exists about the optimum method for detecting underlying paroxysmal AF not apparent on presentation with stroke. The aim of this study was to characterize the rate, timing, and predictors of delayed detection of AF after stroke. METHODS: The Virtual International Stroke Trials Archive provided data from 3464 patients in the placebo arms of 4 clinical trials of therapies for acute ischemic stroke. Patients who had AF by history or on the baseline electrocardiogram were excluded. Electrocardiograms were obtained routinely and as clinically indicated. The time to detection of AF was evaluated using Kaplan-Meier survival statistics. Cox proportional hazards analysis was used to evaluate risk factors for AF. RESULTS: Among 2504 qualifying patients, AF was detected in 174 (6.9%; 95% confidence interval [CI] 6.0%-8.0%). In 68% of patients, AF was detected more than 48 hours after presentation. Detection of AF was associated with increasing age (hazard ratio [HR] 1.6/decade; 95% CI 1.4-1.9; P < .005), female sex (HR 1.7; CI 1.2-2.4; P < .005), congestive heart failure (HR 1.9; CI 1.1-3.4; P = .02), and the absence of hypertension (HR 1.6; CI 1.1-2.2; P = .01). CONCLUSIONS: Delayed detection of AF was common in this large cohort of patients carefully monitored after ischemic stroke. Current methods of screening may fail to detect underlying paroxysmal AF in a substantial proportion of patients.

Serum calcium as prognosticator in ischemic stroke.

BACKGROUND AND PURPOSE: Calcium (Ca(2+)) plays a role in the cellular and molecular pathways of ischemic neuronal death. We evaluated the impact of both early and delayed Ca(2+) levels on clinical outcomes from acute ischemic stroke. METHODS: The relations between blood calcium level obtained early (<4.5 hours), and delayed (72 to 96 hours) after ischemic stroke onset versus clinical outcomes were analyzed in 826 subjects enrolled in an international trial in the Virtual International Stroke Trials Archive. Subjects were categorized into Ca(2+) quartiles. Outcome measures analyzed included baseline and 72- to 96-hour stroke severity, as well as 3-month functional and global disability scales. The independent effect of calcium on outcome was evaluated by median and logistic regression analysis. RESULTS: Six hundred and fifty-nine (80%) of the trial subjects had complete baseline data including Ca(2+) levels. Bivariately, the highest delayed Ca(2+) quartile (versus lowest) was associated with lesser stroke severity and better 3-month functional and independence scale outcomes (all P<0.001), but no significant outcome differences were noted among early Ca(2+) levels. In multivariable analysis, delayed Ca(2+) in the highest quartile (versus lowest quartile) was associated with greater 3-month independence score on the Barthel Index scale (76.9 versus 55.4, P=0.006). No other significant outcome differences were noted between highest and lowest quartiles for both early and delayed Ca(2+) quartiles. CONCLUSIONS: Elevated 72- to 96-hour serum Ca(2+) levels independently predict greater independence 3 months after ischemic stroke, but very early serum Ca(2+) appear not to have any prognostic significance.

Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II).

BACKGROUND AND PURPOSE: A previous randomized, placebo-controlled, double-blind study suggested that abciximab may be safe and effective in treatment of acute ischemic stroke. The current phase 3 study was planned to test the relative efficacy and safety of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset. METHODS: An international, randomized, placebo-controlled, double-blind phase 3 trial tested intravenous administration of abciximab in 2 study cohorts using stratification variables of time since onset and stroke severity. The planned enrollment was 1800 patients. The primary cohort enrolled those patients who could be treated within 5 hours of onset of stroke. A companion cohort enrolled patients that were treated 5 to 6 hours after stroke as well as a smaller cohort of patients who could be treated within 3 hours of stroke present on awakening. The primary efficacy measure was the dichotomous modified Rankin Scale score at 3 months as adjusted to the baseline severity of stroke among subjects in the primary cohort. The primary safety outcome was the rate of symptomatic or fatal intracranial hemorrhage that occurred within 5 days of stroke. RESULTS: The trial was terminated prematurely after 808 patients in all cohorts were enrolled by recommendation of an independent safety and efficacy monitoring board due to an unfavorable benefit-risk profile. At 3 months, approximately 33% of patients assigned placebo (72/218) and 32% of patients assigned abciximab (71/221; P=0.944) in the primary cohort were judged to have a favorable response to treatment. The distributions of outcomes on the modified Rankin Scale were similar between the treated and control groups. Within 5 days of enrollment, approximately 5.5% of abciximab-treated and 0.5% of placebo-treated patients in the primary cohort had symptomatic or fatal intracranial hemorrhage (P=0.002). The trial also did not demonstrate an improvement in outcomes with abciximab among patients in the companion and wake-up cohorts. Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6% versus 5% for placebo). CONCLUSIONS: This trial did not demonstrate either safety or efficacy of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke regardless of end point or population studied. There was an increased rate of symptomatic or fatal intracranial hemorrhage in the primary and wake-up cohorts.

Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study.

BACKGROUND: The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. METHODS: Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062. FINDINGS: 20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups. INTERPRETATION: Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.